The immune system, particularly cytotoxic T lymphocytes (which, hereinafter, may be abbreviated to CTLs) play an important role in the exclusion of cancer in vivo. An infiltration of cytotoxic T lymphocytes that exhibit a toxic activity against a tumor cell has been detected at the tumor site of a cancer patient (Arch. Surg., 126: 200-205, 1990). A tumor antigen that is a target molecule for the tumor-specific cytotoxic T lymphocytes was first discovered in melanoma type cancers. A tumor antigen generated in a tumor cell is decomposed in the cell into a peptide (tumor antigen peptide) consisting of eight to eleven amino acids, which binds to a human leukocyte antigen (HLA) molecule that is the major histocompatibility complex to be displayed on the surface of the tumor cell.
HLA is a cell membrane antigen, and is expressed on almost all of eukaryotic cells. HLA is mainly classified as a class I antigen or class II antigen. The HLA recognized together with an antigen peptide by a cytotoxic T lymphocytes is a class I antigen. HLA class I antigens are further classified into HLA-A, B, C, and so on. It was reported that HLA has the genetic polymorphism. The HLA-A24 allele is found in approximately 60% of the Japanese population (in a majority, equal to 95%, the genotype is A2402), 20% of Caucasians, and 12% of Africans. The HLA-A2 allele is found in approximately 40% of Japanese, 53% of Chinese, 49% of North Caucasians, 38% of South Caucasians, and 23% of Black Africans.
A tumor antigen peptide capable of binding to the HLA has a motif in its sequence for each type of HLA. Cytotoxic T lymphocytes injure a tumor cell by recognizing a complex consisting of the tumor antigen peptide and HLA. As used herein, a tumor antigen means a protein or peptide contained in a tumor cell capable of inducing a tumor-specific cytotoxic T lymphocyte. A tumor antigen peptide means a peptide that is generated as a result of degradation of the tumor antigen in a tumor cell and can induce or activate tumor-specific cytotoxic T lymphocytes by being expressed on the surface of the cells by binding an HLA molecule. In addition, a site of the amino acid sequence capable of inducing tumor-specific cytotoxic T lymphocytes existing in a tumor antigen is called a tumor antigen epitope (tumor antigen determinant).
Recently, many genes encoding tumor antigens that can be recognized by cytotoxic T lymphocytes have been identified from cDNA of human tumor cells (Science, 254: 1643-1647, 1991; J. Exp. Med., 183: 1185-1192, 1996). Some of these genes are involved in cell proliferation and malignant transformation, including HER/neu (Proc. Natl. Acad. Sci. USA, 92: 432-436, 1995), mutant cdk (Science, 269, 1281-1284, 1995), and mutant CASP-8 (J. Exp. Med., 186: 785-793, 1997). Several other gene products such as MAGE (melanoma antigen) family (Cancer Res., 55: 3478-3482, 1995) and SART1 (J. Exp. Med. 187: 277-288, 1998) are preferentially expressed in both of malignant cells and the testis, but not in other normal cells.
Many melanoma-specific tumor antigens exist also in a normal melanocyte, including MART-1/melanA, gp100, and tyrosinase (Oncogene Res., 1: 357-374, 1987). Therefore, human tumor antigens are for the most part not truly tumor-specific antigens, but rather self-antigens that are expressed in some normal cells or tissues.
Now, in Europe and in the United States, a cancer vaccine therapy has been developed that activates cytotoxic T lymphocytes in a cancer patient by an administration of a tumor antigen peptide, and the results of clinical tests have been reported with respect to the melanoma-specific tumor antigen. For example, tumor regression has been observed in 42% of melanoma patients who received the subcutaneous injection of melanoma antigen gp100 peptide and intravenous injection of interleukin-2 (IL-2) (Nature Medicine, 4: 321, 1998). Thus, by utilizing a tumor antigen as a vaccine, an effective treatment against cancer can be achieved.
However, almost all of the identified tumor antigens are derived from melanoma, and only a few papers have been published on tumor antigens derived from epithelial cancer and adenocarcinoma, which occur at high incidence rates.
Five-year survival rate due to three known major treatment methods for cancer (operation therapy, chemotherapy, and irradiation treatment) was 41% in 1998 with respect to all kinds of cancer. However, it is so far difficult to increase the survival rate, so that the development of a new treatment method is desired other than the above-mentioned three major treatment methods.
The lck gene encoding p56lck protein, which is an src family membrane tyrosine kinase, has an essential role in T cell development and function. Abnormal expression of the lck gene in colon cancer cells and small lung carcinoma cells (Oncogene Res., 1: 357-374, 1987) and aberrant expression in metastatic colon cancer were reported. However, detailed roles of Lck protein in these cancer cells are still unknown, although it is suggested that Lck protein plays an important role in the process of neoplastic transformation (Cancer Res., 58: 4660-4666, 1998),